Abstract
BackgroundIn humans and animal models, excessive intake of dietary fat, fructose and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD). However, the individual roles of the dietary components remain unclear. To investigate this further, we compared the effects of a high-fat diet, a high-fructose diet and a combination diet with added cholesterol on the development of NAFLD in rats.MethodsForty male Sprague–Dawley rats were randomized into four groups receiving either a control-diet (Control: 10% fat); a high-fat diet (HFD: 60% fat, 20% carbohydrate), a high-fructose diet [HFr: 10% fat, 70% carbohydrate (mainly fructose)] or a high-fat/high-fructose/high-cholesterol-diet (NASH: 40% fat, 40% carbohydrate (mainly fructose), 2% cholesterol) for 16 weeks.ResultsAfter 16 weeks, liver histology revealed extensive steatosis and inflammation in both NASH- and HFD-fed rats, while hepatic changes in HFr-rats were much more subtle. These findings were corroborated by significantly elevated hepatic triglyceride content in both NASH- (p < 0.01) and HFD-fed rats (p < 0.0001), elevated hepatic cholesterol levels in NASH-fed rats (p < 0.0001), but no changes in HFr-fed rats, compared to Control. On the contrary, only HFr-fed rats developed dyslipidemia as characterized by higher levels of plasma triglycerides compared to all other groups (p < 0.0001). Hepatic dysfunction and inflammation was confirmed in HFD-fed rats by elevated levels of hepatic MCP-1 (p < 0.0001), TNF-alpha (p < 0.001) and plasma β-hydroxybutyrate (p < 0.0001), and in NASH-fed rats by elevated levels of hepatic MCP-1 (p < 0.01), increased hepatic macrophage infiltration (p < 0.001), and higher plasma levels of alanine aminotransferase (p < 0.0001) aspartate aminotransferase (p < 0.05), haptoglobin (p < 0.001) and TIMP-1 (p < 0.01) compared to Control.ConclusionThese findings show that dietary fat and cholesterol are the primary drivers of NAFLD development and progression in rats, while fructose mostly exerts its effect on the circulating lipid pool.
Highlights
In humans and animal models, excessive intake of dietary fat, fructose and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD)
Baseline characteristics for Control, high-fat diet (HFD), high-fructose diet (HFr) and non-alcoholic steatohepatitis (NASH)-groups are given in Table 2 and show that groups were comparable at study start for all parameters
After 8 weeks, accumulated energy intake was significantly higher in NASH-fed rats, compared to both Controland HFr-fed rats (p < 0.001 and p < 0.05, Fig. 1c) and in HFD-fed rats compared to Control (p < 0.05)
Summary
In humans and animal models, excessive intake of dietary fat, fructose and cholesterol has been linked to the development of non-alcoholic fatty liver disease (NAFLD). The individual roles of the dietary components remain unclear To investigate this further, we compared the effects of a high-fat diet, a high-fructose diet and a combination diet with added cholesterol on the development of NAFLD in rats. Even though the specific etiology of NAFLD remains unclear, dietary fat and cholesterol have been linked to the development of hepatic steatosis and NASH in both humans and animal models [12,13,14] and more recently, the marked increase in consumption of the simple carbohydrate fructose, has been pointed out as another possible contributory factor [15, 16]. Establishment of animal models of NAFLD/NASH that more adequately mimic human pathology will be valuable when testing novel therapeutics for NAFLD/NASH
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